Abstract
Calcineurin (CN) is a Ca2+/calmodulin-dependent protein phosphatase expressed at high levels in brain. Many findings have shown that calcineurin plays an important role in tau hyperphosphorylation, which is one of the neuropathologic features in the brains of Alzheimer’s disease (AD). Based on the molecular screening model using p-nitrophenyl phosphate (p-NPP) as a substrate for preliminary screening and 32P-labeled 19-residue phosphopeptide as a specific substrate for final determination, we found that the total ginsenoside extracts from stems and leaves of Panax ginseng (GSL) could enhance the phosphatase activity of purified CN. In the human neuroblastoma cells SY5Y, inhibition of CN by cyclosporine A (CsA) could induce hyperphosphorylation of tau at multiple sites, accompanied with oxidative stress. Pretreatment of the cells with GSL prior to CsA exposure could alleviate CsA-induced CN inhibition and tau hyperphosphorylation to some degree. Further oxidative parameters demonstrated that GSL caused increased SOD activity and content of SH significantly. It is speculated that GSL weakens CsA-induced CN inhibition through the antioxidant mechanisms. Although our results indicate that GSL may have neuroprotective effects on some characteristic features of AD, the chemical compositions of GSL and their potential for affecting the disease mechanism need to be further studied.
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References
Ahmed SS, Strobel HW, Napoli KL, Grevel J (1993) Adrenochrome reaction implicates oxygen radicals in metabolism of cyclosporin A and FK506 in rat and human liver microsomes. J Pharmacol Exp Ther 265:1047–1054
Anekonda TS, Reddy HP (2005) Can herbs provide a new generation of drugs for treating Alzheimer’s disease? Brain Res Brain Res Rev 50:361–376
Chen F, Eckman EA, Eckman CB (2006) Reductions in levels of the Alzheimer’s amyloid β peptide after oral administration of ginsenosides. FASEB J 20:1269–1271. doi:10.1096/fj.05-5530fje
Fruman DA, Klee CB, Bierer BE, Burakoff SJ (1992) Calcineurin phosphatase activity in T lymphocytes is inhibited by FK506 and cyclosporin A. Proc Natl Acad Sci USA 89:3686–3690. doi:10.1073/pnas.89.9.3686
Fruman DA, Pai SY, Klee CB, Burakoff SJ, Bierer BE (1996) Measurement of calcineurin phosphatase activity in cell extracts. Methods 9:146–154. doi:10.1006/meth.1996.0020
Furuke K, Shiraishi M, Mostowski HS, Bloom ET (1999) Fas ligand induction in human NK cells is regulated by redox through a calcineurin-nuclear factors of activated T cell-dependent pathway. J Immunol 162:1988–1993
Goedert M (1993) Tau protein and the neurofibrillary pathology of Alzheimer’s disease. Trends Neurosci 16:460–465. doi:10.1016/0166-2236(93)90078-Z
Jiang GH, Wei Q (2003) Function and structure of N-terminal and C-terminal domains of calcineurin B subunit. Biol Chem 384:1299–1303. doi:10.1515/BC.2003.145
Johnson GVW, Stoothoff WH (2004) Tau phosphorylation in neuronal cell function and dysfunction. J Cell Sci 117:5721–5729. doi:10.1242/jcs.01558
Kayyali US, Zhang W, Yee AG, Seidman JG, Potter H (1997) Cytoskeletal change in the brains of mice lacking calcineurin Aα. J Neurochem 68:1668–1678
King MM (1986) Modification of the calmodulin-stimulated phosphatase, calcineurin, by sulfhydryl reagents. J Biol Chem 261:4081–4084
Liu J, Farmer JD Jr, Lane WS, Friedman J, Weissman I, Schreiber SL (1991) Calcineurin is a common target of cyclophilin-cyclosporin A and FKBP-FK506 complexes. Cell 66:807–815. doi:10.1016/0092-8674(91)90124-H
Luo J, Yin JH, Wei Q (2003) The effect of a calcineurin activator, extracted from Chinese herbal medicine on memory and immunity in mice. Pharmacol Biochem Behav 75:749–754. doi:10.1016/S0091-3057(03)00148-5
Nie BM, Jiang XY, Cai JX, Fu SL, Yang LM, Lin L, Hang Q, Lu PL, Lu Y (2008) Panaxydol and panaxynol protect cultured cortical neurons against Aβ 25–35-induced toxicity. Neuropharmacology 54:845–853. doi:10.1016/j.neuropharm.2008.01.003
Perrino BA, Fong YL, Brickey DA, Saitoh Y, Ushio Y, Fukunaga K, Miyamoto E, Soderling TR (1992) Characterization of the phosphatase activity of a baculovirus-expressed calcineurin A isoform. J Biol Chem 267:15965–15969
Stemmer PM, Wang X, Krinks MH, Klee CB (1995) Factors responsible for the Ca2+-dependent inactivation of calcineurin in brain. FEBS Lett 374:237–240. doi:10.1016/0014-5793(95)01095-V
Tong L, Song Y, Jia ZG, Zhang W, Wei Q (2007) Calmodulin-dependent activation of calcineurin by chlorogenic acid. IUBMB Life 59:402–407. doi:10.1080/15216540701411244
Wang X, Culotta VC, Klee CB (1996) Superoxide dismutase protects calcineurin from inactivation. Nature 383:434–437. doi:10.1038/383434a0
Wang HL, Du YW, Xiang BQ, Lin WL, Wei Q (2007) The regulatory domains of CNA have different effects on the inhibition of CN activity by FK506 and CsA. IUBMB Life 6:388–393. doi:10.1080/15216540701370721
Wei Q, Holzer M, Brueckner MK, Liu Y, Arendt T (2002) Dephosphorylation of tau protein by calcineurin(PP2B) led to neural living cells. Cell Mol Neurobiol 22:13–24. doi:10.1023/A:1015385527187
Wolf A, Trendelenburg CF, Diez-Fernandez C, Prieto P, Houy S, Trommer WE, Cordier A (1997) Cyclosporine A-induced oxidative stress in rat hepatocytes. J Pharmacol Exp Ther 280:1328–1334
Wolff DJ, Sved DW (1985) The divalent cation dependence of bovine brain calmodulin-dependent phosphatase. J Biol Chem 260:4195–4202
Wu HZ, Luo J, Yin YX, Wei Q (2004) Effects of chlorogenic acid, an active compound activating calcineurin, purified from Flos lonicerae on macrophage. Acta Pharmacol Sin 25:1685–1689
Xiang BQ, Liu P, Jiang GH, Zou K, Yi F, Yang SJ, Wei Q (2003) The catalytically active domain in the A subunit of calcineurin. Biol Chem 384:1429–1434. doi:10.1515/BC.2003.158
Yamamoto T, Yuyama K, Nakamura K, Kato T, Yamamoto H (2000) Kinetic characterization of the nitric oxide toxicity for pc12 cells: effect of half-life time of no release. Eur J Pharmacol 397:25–33. doi:10.1016/S0014-2999(00)00244-2
Yan LJ, Wei Q (1999) High activity of the calcineurin A subunit with a V314 deletion. Biol Chem 38:1281–1285. doi:10.1515/BC.1999.163
Yan LJ, Yu CJ, Wei Q (2000) Effect of different immunosuppressive drugs on calcineurin and its mutants. Sci China C Life Sci 43:68–74. doi:10.1007/BF02881719
Yu DY, Luo J, Bu F, Song GJ, Wei Q (2006a) Inhibition of calcineurin by infusion of CsA causes hyperphosphorylation of tau, accompanied by abnormal behavior in mice. Biol Chem 387:977–983. doi:10.1515/BC.2006.121
Yu DY, Luo J, Bu F, Zhang W, Wei Q (2006b) Effects of Cyclosporin A, FK506 and rapamycin on calcineurin phosphatase activity in mouse brain. IUBMB Life 58:429–433. doi:10.1080/15216540600791555
Acknowledgments
We thank Prof. Qun Wei for the groundwork of calcineurin and helpful comments. We thank the National Nature Science Foundation of China for funding the Project 30772558, J0630642 and the Analytical and Testing Foundation of Beijing Normal University.
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Tu, LH., Ma, J., Liu, HP. et al. The Neuroprotective Effects of Ginsenosides on Calcineurin Activity and Tau Phosphorylation in SY5Y Cells. Cell Mol Neurobiol 29, 1257–1264 (2009). https://doi.org/10.1007/s10571-009-9421-3
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DOI: https://doi.org/10.1007/s10571-009-9421-3